rs763295984
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4
The NM_144599.5(NIPA1):c.403G>A(p.Val135Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
NIPA1
NM_144599.5 missense
NM_144599.5 missense
Scores
4
2
Clinical Significance
Conservation
PhyloP100: 4.81
Genes affected
NIPA1 (HGNC:17043): (NIPA magnesium transporter 1) This gene encodes a magnesium transporter that associates with early endosomes and the cell surface in a variety of neuronal and epithelial cells. This protein may play a role in nervous system development and maintenance. Multiple transcript variants encoding different isoforms have been found for this gene. Mutations in this gene have been associated with autosomal dominant spastic paraplegia 6. [provided by RefSeq, Nov 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 15-22820398-G-A is Pathogenic according to our data. Variant chr15-22820398-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 533363.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.28805184). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NIPA1 | NM_144599.5 | c.403G>A | p.Val135Met | missense_variant | 4/5 | ENST00000337435.9 | |
NIPA1 | NM_001142275.1 | c.178G>A | p.Val60Met | missense_variant | 4/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NIPA1 | ENST00000337435.9 | c.403G>A | p.Val135Met | missense_variant | 4/5 | 1 | NM_144599.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460162Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1AN XY: 726528
GnomAD4 exome
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1
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1460162
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29
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1
AN XY:
726528
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
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33
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hereditary spastic paraplegia 6 Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Paris Brain Institute, Inserm - ICM | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 135 of the NIPA1 protein (p.Val135Met). This variant is present in population databases (rs763295984, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with NIPA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 533363). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
MetaRNN
Benign
T;T;T
PROVEAN
Uncertain
N;N;N
Sift
Benign
D;D;D
Vest4
RBP_binding_hub_radar
RBP_regulation_power_radar
gMVP
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at